Cardiac Arrest, or Sudden Death, is a descriptor for a diverse collection of physiological abnormalities with a common cardiac etiology, wherein the patient typically presents with the symptoms of pulselessness, apnea and unconsciousness. Cardiac arrest is widespread, with an estimated 300,000 victims annually in the U.S. alone and a similar estimate of additional victims worldwide. Early defibrillation is the major factor in sudden cardiac arrest survival. There are, in fact, very few cases of cardiac arrest victims saved which were not treated with defibrillation. There are many different classes of abnormal electrocardiographic (ECG) rhythms, some of which are treatable with defibrillation and some of which are not. The standard terminology for this is “shockable” and “non-shockable” ECG rhythms, respectively. Non-shockable ECG rhythms are further classified into hemodynamically stable and hemodynamically unstable rhythms. Hemodynamically unstable rhythms are those which are incapable of supporting a patient's survival with adequate blood flow (non-viable). For example, a normal sinus rhythm is considered non-shockable and is hemodynamically stable (viable). Some common ECG rhythms encountered during cardiac arrest that are both non-shockable and hemodynamically unstable are: bradycardia, idioventricular rhythms, pulseless electrical activity (PEA) and asystole. Bradycardias, during which the heart beats too slowly, are non-shockable and also possibly non-viable. If the patient is unconscious during bradycardia, it can be helpful to perform chest compressions until pacing becomes available. Idioventricular rhythms, in which the electrical activity that initiates myocardial contraction occurs in the ventricles but not the atria, can also be non-shockable and non-viable (usually, electrical patterns begin in the atria). Idioventricular rhythms typically result in slow heart rhythms of 30 or 40 beats per minute, often causing the patient to lose consciousness. The slow heart rhythm occurs because the ventricles ordinarily respond to the activity of the atria, but when the atria stop their electrical activity, a slower, backup rhythm occurs in the ventricles. Pulseless Electrical Activity (PEA), the result of electromechanical dissociation (EMD), in which there is the presence of rhythmic electrical activity in the heart but the absence of myocardial contractility, is non-shockable and non-viable and would require chest compressions as a first response. Asystole, in which there is neither electrical nor mechanical activity in the heart, cannot be successfully treated with defibrillation, as is also the case for the other non-shockable, non-viable rhythms. Pacing is recommended for asystole, and there are other treatment modalities that an advanced life support team can perform to assist such patients, e.g. intubation and drugs. The primary examples of shockable rhythms that can be successfully treated with defibrillation are ventricular fibrillation, ventricular tachycardia, and ventricular flutter.
Normally, electrochemical activity within a human heart causes the organ's muscle fibers to contract and relax in a synchronized manner. This synchronized action of the heart's musculature results in the effective pumping of blood from the ventricles to the body's vital organs. In the case of ventricular fibrillation (VF), however, abnormal electrical activity within the heart causes the individual muscle fibers to contract in an unsynchronized and chaotic way. As a result of this loss of synchronization, the heart loses its ability to effectively pump blood. Defibrillators produce a large current pulse that disrupts the chaotic electrical activity of the heart associated with ventricular fibrillation and provides the heart's electrochemical system with the opportunity to re-synchronize itself. Once organized electrical activity is restored, synchronized muscle contractions usually follow, leading to the restoration of effective cardiac pumping.
First described in humans in 1956, transthoracic defibrillation has become the primary therapy for cardiac arrest, ventricular tachycardia (VT), and atrial fibrillation (AF). Monophasic waveforms dominated until 1996, when the first biphasic waveform became available for clinical use. Attempts have also been made to use multiple electrode systems to improve defibrillation efficacy. While biphasic waveforms and multiple-electrode systems have shown improved efficacy relative to monophasic defibrillation, there is still significant room for improvement: shock success rate for ventricular fibrillation (VF) remains less than 70% even with the most recent biphasic technology. In these cases, shock success was defined to be conversion of a shockable rhythm into a non-shockable rhythm, including those non-shockable rhythms which are also non-viable. Actual survival-to-hospital-discharge rates remain an abysmal ten percent or less. Survival rates from cardiac arrest remain as low as 1-3% in major U.S. cities, including those with extensive, advanced prehospital medical care infrastructures.
The initial rhythm following a defibrillation shock is rarely a perfusing, viable rhythm and almost always is asystole or PEA, neither of which is treatable with defibrillation. In addition, recent studies have shown rates of ventricular fibrillation (VF) and shockable ventricular tachycardias (VT) to be unexpectedly low. A recent report from Goteborg, Sweden shows VF to be present in only 39% of cases. Similar results have been reported from Seattle and Ontario, Canada. Ornato et al in a study of hospital cardiac arrest found only 25% of patients presented with a shockable rhythm (VF/VT); 66% presented with non-shockable rhythms asystole and PEA. There is even retrospective clinical data that indicates that the rates of non-shockable PEA and asystole are increasing in cardiac arrest victims.
Given that neither of these rhythms is treatable with defibrillation, there is a justifiable clinical concern that the treatment protocols currently recommended by expert groups such as the American Heart Association are inadequate. A recent publication by Ewy proposed that certain elements of the present AHA guidelines [AHA Guidelines 2000 for CPR and Emergency Cardiovascular Care, Circulation 2000; 102(8), Supplement] regarding Basic and Advanced Life Support (BLS, ALS) field protocols may be contributing factors in the poor survival rates for cardiac arrest. The term basic life support (BLS) refers to maintaining airway patency and supporting breathing and circulation without the use of equipment other than a protective shield. BLS comprises the elements: initial assessment; airway maintenance; expired air ventilation (rescue breathing); and chest compression. When all three (airway breathing, circulation) are combined the term cardiopulmonary resuscitation (CPR) is used. Personnel trained in ALS will also deliver drugs, as well as such advanced techniques as intubation, administration of intravenous fluids and suturing in addition to BLS techniques. In the currently recommended treatment protocols, BLS personnel should perform CPR on cardiac arrest victims whose rhythm is either PEA or asystole; ALS personnel have the additional treatments available of intubation, intravenous administration and the drugs epinephrine and atropine. None of these ALS techniques, however, have been particularly effective in the treatment of either PEA or asystole. Assuming a rate of PEA and asystole of 66% in cardiac arrest victims, 400,000 of the 600,000 total worldwide cardiac arrest victims would present in physiological states for which there was no effective treatment for their condition, which has a 0% survival rate, it should be noted, if left untreated.
A new protocol, coined “CPR First”, is being considered which reemphasizes the importance of perfusion. It is currently proposed as follows: for patients with a known (witnessed) collapse time of less than 4 minutes, perform the present field protocol; for patients with prolonged (greater than 4 minutes) or unknown collapse time, (1) immediately begin uninterrupted chest compressions prior to a defibrillation shock (various lengths of time for compression are being considered, starting with 90 seconds or greater), (2) only apply one defibrillation shock (e.g., a biphasic waveform) at the end of the first chest compression cycle, and (3) followed immediately by 200 uninterrupted chest compressions prior to a cardiac rhythm analysis by an automated external defibrillator (AED) or by the rescuer trained in the analysis of ECG rhythms, providing a defibrillation shock as necessary (repeat steps 1-3 for as long as deemed necessary). As long as the patient remains unconscious, the rescuer can alternate between use of the defibrillator (for analyzing the electrical rhythm and possibly applying a shock) and performing cardiopulmonary resuscitation (CPR). CPR generally involves a repeating pattern of five or fifteen chest compressions followed by providing the victim with a number of breaths. CPR is generally ineffective against abnormal rhythms, but it does keeps some level of oxygenated blood flow going to the patient's vital organs until an advanced life support team arrives.
The treatment window for cardiac arrest is very narrow. Long term survival rates from the time of victim collapse decrease at a roughly exponential rate with a time constant of roughly 2 minutes. Thus, just two minutes of delay in treatment using the currently recommended treatment protocols result in a long term survival rate of 30-35%. After 15 minutes, the long term survival rates are below 5%. While the response times of emergency medical systems have improved significantly over the last quarter century to the point that average times from emergency call to arrival at the victim is typically 9 minutes or less, bystander delays in making the emergency call typically add 2-3 minutes to the total arrest time, for a total of 11-12 minutes. In addition, the bystander making the emergency call may not even have witnessed the cardiac arrest, which may have occurred at some point in the past. Unwitnessed arrest accounts for at least half of all cardiac arrests. Cardiac arrest downtimes are only reported for witnessed arrests; it has been estimated, however, that if unwitnessed arrests were to be included, the average downtime for all victims would exceed 15 minutes. At the time of initial collapse, the ECGs of nearly all cardiac arrest victims are shockable rhythms such as VF or VT; after 15 minutes, however, the ECG rhythms of most cardiac arrest victims have degenerated into the non-shockable rhythms of PEA or asystole.
Excitation-Contraction (E-C) coupling describes the process by which the electrical signal, initiated in the S-A node in normal hearts, is converted to a mechanical contraction in the myocardial cells. Excitation-contraction coupling begins when an action potential depolarizes the plasma membrane surrounding the myocardial cell, which generates an electrical signal by allowing ions to flow through ion-selective channels in the plasma membrane. Two cations, sodium and calcium, carry the inward currents that depolarize the heart, while the cation potassium carries the outward current that repolarizes the heart and is the primary determinant of the heart's resting potential. Excitation of the cells of the atria and ventricles begins when opening of the sodium channels generates an inward (depolarizing) sodium current. The resulting change in membrane potential opens calcium channels that trigger calcium release from the sarcoplasmic reticulum.
Calcium ions, by carrying signals generated at the cell surface to a variety of intracellular proteins and organelles, can be viewed as the most important of the intracellular messengers. Myocardial cells use calcium as the essential final step in excitation-contraction coupling, the process by which depolarization at the cell surface initiates the interactions between the contractile proteins that cause the walls of the heart to develop tension and contract.
Calcium binding to troponin-C triggers interactions between actin and myosin by reversing an inhibitory effect of the regulatory proteins. This response begins with a series of cooperative interactions between calcium-bound troponin-C and other proteins of the thin filaments: actin, tropomyosin, troponin-I, and troponin-T. Calcium binding to troponin-C weakens the bond linking troponin-I to actin, causing a structural rearrangement of the regulatory proteins that shifts the tropomyosin deeper into the grooves between the strands of actin. This rearrangement exposes active sites on actin for interaction with the myosin cross bridges.
The ultrastructure of the myocardial cell is shown in FIG. 1. The sarcomere is the functional unit of the contractile apparatus. The sarcomere is defined as the region between the successive Z-lines and contains two half-I-bands and one A-band. Contractile proteins are arranged in a regular array of thick and thin filaments (seen in cross section at the left). The A-band represents the region of the sarcomere occupied by the thick filaments into which the thin filaments extend from either side. The I-band is the region of the sarcomere occupied only by the thin filaments; these extend toward the center of the sarcomere from the Z-lines, which bisect each I-band. The sacroplasmic reticulum, a membrane network that surrounds the contractile proteins, consists of the sarcotubular network at the center of the sarcomere and the cisternae, which abut the t-tubules and the sarcolemma, so that the lumen of the t-tubules carries the extracellular space toward the center of the myocardial cell.
At rest, active transport processes (mainly the sodium-potassium pump) maintain electrochemical gradients across the sarcolemmal membrane. Consequently, a resting membrane potential is established with the cell interior being negative relative to the extracellular space. Depolarization of the cardiac sarcolemmal membrane occurs largely due to opening of sodium channels, which results in an influx of sodium and a rapid rise in membrane potential from negative to positive values. This change in membrane potential is ultimately translated into an increase in intracellular cytosolic calcium, binding of calcium to the contractile protein complex in the myofibrils, and cell shortening (contraction). Relaxation occurs as the resting sarcolemmal membrane potential is reestablished, intracellular cytosolic calcium decreases, and calcium dissociates from the contractile protein complex.
FIG. 2, shows the primary calcium fluxes of both the E-C coupling and relaxation. The thickness of each arrow represents the magnitude of the calcium flux, and their vertical orientation describe whether or not the flux is generated by passive or active transport: downwardly-directed arrows represent passive flux while upwardly-directed arrows represent energy-dependent active calcium transport. Most of the calcium that enters the cell from the extracellular fluid via the L-type calcium channels (arrow A) triggers calcium release from the sacroplasmic reticulum; only a small portion directly activates the contractile proteins (arrow A1). Calcium is actively transported back into the extracellular fluid by the plasma membrane calcium pump ATPase (arrow B1) and the Na/Ca exchanger (arrow B2). The sodium that enters the cell in exchange for calcium (dashed line) is pumped out of the cytosol by the sodium pump. The channels providing inward-directed calcium flux are: 1) L-type channels, located in the transverse tubular system, in close proximity to the calcium release channels of the sarcoplasmic reticulum; and 2) T-type channels not concentrated in t-tubules but can be found on the plasma membrane of the myocardial cells. The channels providing outward-directed calcium flux are: 1) plasma membrane calcium pump (PMCA), a low volume pump; and 2) the Na/Ca exchanger.
Calcium entry via L-type calcium channels is among the most important determinants of myocardial contractility. This calcium entry serves two functions: it triggers the opening of the intracellular calcium release channels in the sarcoplasmic reticulum and provides most of the activator calcium that binds to troponin, and it fills the internal calcium stores. Only a small amount binds directly to the contractile proteins of the adult heart, which depends mainly on the intracellular calcium cycle. B-adrenergic agonists are known to increase L-type channel flow, while both calcium and beta-channel blockers are known to inhibit calcium flux through the L-type calcium channels.
The Na/Ca exchanger transports three sodium ions in one direction across the membrane for a single calcium ion that moves in the opposite direction, which means that the Na/Ca exchange is electrogenic. Therefore, calcium efflux, which relaxes the heart, is favored during diastole, whereas calcium influx increases contractility during systole.
Two calcium fluxes are regulated by the sacroplasmic reticulum: calcium efflux from the sarcolemmal cisternae via calcium release channels (arrow C) and calcium uptake into the sarcotubular network by the sarco(endo)plasmic reticulum calcium pump ATPase (arrow D). Calcium diffuses within the sacroplasmic reticulum from the sarcotubular network to the sarcolemmal cisternae (arrow G), where it is stored in a complex with calsequestrin and other calcium-binding proteins. Calcium binding to (arrow E) and dissociation from (arrow F) high-affinity calcium binding sites of troponin-C activate and inhibit the interactions of the contractile proteins. Calcium movements in and out of the mitochondria (arrow H) buffer cytosolic calcium concentration. The extracellular calcium cycle consists of arrows A, B1, and B2, whereas the intracellular cycle involves arrows C, D, E, F, and G.
In addition, the relaxation cycle of diastole is regulated primarily by calcium uptake by the sarco(endo)plasmic reticulum calcium(SERCA) pump (arrow D) and calcium uptake by the mitochondria (arrow H), which together provide the function of normalizing and stabilizing cytosolic calcium levels.
The most distinctive phase of the cardiac action potential is the plateau phase, generally termed phase 2 (phase 0 is the action potential upstroke, phase 1 is the early depolarization, phase 3 is the repolarization phase, and phase 4 is diastole) generated by counterbalancing ionic fluxes of an inward cardiac current and outward potassium current. The major role of the plateau is to prevent the heart from being reactivated before the ventricles have had time to fill after the preceding systole. It is calcium flux generated by L-type channels that provides the important duration extension of phase 2.
It is well known to those skilled in the art that the sustained energy demands of the heart can be met only by the mechanism of oxidative phosphorylation, which requires that the coronary circulation deliver an uninterrupted supply of the metabolic substrates, notably oxygen. The myocardial ischemia induced by cardiac arrest has a number of important metabolic effects. In addition to the prevention of the delivery of oxygen to the myocardial cells, there is an accumulation of protons (H+) and lactate. The resulting acidosis inhibits glycolysis and adversely affects contractility. Further, phosphate and potassium accumulate which contribute to arrhythmogenesis and reduced contractility. Cytosolic calcium concentrations increase during ischemia due to the reduced cytosolic calcium uptake into the sarcotubular network by the SERCA pump, caused by lowered ATP levels within the ischemic milieu. During the early stages of ischemia, approximately <20 minutes, the Na/Ca exchanger gradually drains the calcium from the cytosol. While cytosolic concentrations of calcium may be higher due to the reduced function on the SERCA pump, there is a net depletion of calcium within the cell during ischemia that needs to be ameliorated before heart function can be returned to normal. EC coupling fails under this condition resulting in PEA and asystole. Global myocardial ischemia induced during cardiac arrest has effects related to lack of oxygen, but also effects from the prevention of the removal of metabolites which accumulate in the ischemic heart such as protons (H+), phosphate, potassium and lactate. Acidosis from H+ and lactate inhibits glycolosis and reduces both contractility and relaxation. Potassium contributes to the genesis of arrhythmias while phosphate decreases contractility.
Prior art in defibrillation has focused on the cessation of fibrillation such as U.S. Pat. Nos. 3,460,542, 3,547,108, 3,716,059, 4,088,138 and 4,928,690. Transcutaneous pacing of the heart for treatment of bradycardias as well as asystole and electromechanical dissociation can be found in such prior art as U.S. Pat. No. 4,349,030. U.S. Pat. No. 5,584,866 teaches a method for achieving cardiac output during fibrillation by increasing the amplitude of the pacing stimulus. U.S. Pat. Nos. 5,205,284, 6,253,108 B1, 6,259,949 B1, and 6,263,241 B1 describe the use of higher frequency pulses in the treatment of EMD. U.S. Pat. Nos. 5,314,448 and 6,556,865 B2 both describe the electrical pretreatment of the fibrillating heart in order to improve defibrillation results.